Use of a Dynamic Flow Platform To Translate a Batch Immobilized Transaminase Process to a Packed Bed Reactor for the Synthesis of an Intermediate of Nemtabrutinib
Michael J. Di Maso, Jeffrey T. Kuethe, Karthik Narsimhan, Matthew Burris, Cheol K. Chung, Michael DiBenedetto, Jacob H. Forstater, Shane T. Grosser, Nadine Kuhl, François Lévesque, Anne Maguire, Kevin M. Maloney, Jonathan P. McMullen, Christopher K. Prier, Ji Qi, Nelo R. Rivera, Zhixun Wang, Brian M. Wyvratt, Daniel Zewge
Abstract
Herein we describe the translation of an immobilized transaminase process in batch to a packed bed reactor for the synthesis of cyrene amine, an intermediate of Nemtabrutinib. This change in reactor design provided significant benefits in both robustness of the immobilized enzyme preparation and minimization of the amount of the enzyme required to perform the transformation. The extended residence times required for high conversion led us to investigate a dynamic flow system to quickly survey the reaction kinetics under various conditions and to provide approximate residence times for pseudosteady state runs to determine the lifetime of the enzyme. The immobilized enzyme lifetime was assessed and found to provide high levels of conversion for over 100 h of performance. Ultimately, the process was scaled to provide over a kilogram of the desired amine, isolated as a tosylate salt, and further optimization with an evolved enzyme and translation to larger scales is also discussed.